Glomerular Permeability to Macromolecules
The composition of the fluid which passes the glomerular membrane conforms closely to that of an ideal ultrafiltrate of plasma. A large number of micropuncture experiments agree that the concentration of sodium, chloride, phosphate, urea, glucose, hydrogen ion and uric acid in fluid collected from Bowman’s capsule exceeds by 2-4 per cent the concentration in plasma (Renkin & Gilmore 1973).
After correction for the influence of Donnan effects of the non-filtered protein on charged particles, the concentrations show remarkable conformity with that predicted for a passive, freely permeable membrane. Dextrans and inulin with a molecular weight of 5,000 or less also appear in the filtrate in concentrations which indicate that the membrane is freely permeable to molecules of this size. Conversely, normal plasma proteins are present in the filtrate only in concentrations at the level of the threshold sensitivity for detection.
Bayliss et al. (1933) found in the cat, rabbit and dog that proteins with a molecular weight over 68,000, such as serum albumin and globulins, were not excreted in the urine, whereas smaller proteins such as gelatin, the molecular weight of which ranges from l7,000 to 57,000. Hence-Jones protein with a molecular weight of 40,000, and haemoglobin with a molecular weight of 68,000 appeared in the urine after intravenous administration.
Since that time many studies in animals and in man have demonstrated that molecules which can be administered in graded size, such as dextran or polyvinylpyrrolidone, appear in the urine in approximate relationship to their molecular weight and size (Renkin & Gilmore l973) see also Chapter 13.
Increasing restriction to penetration by solutes of increasing molecular size is a property both of membrane structures which have pores of approximately the dimensions of the solutes in an otherwise impermeable matrix, and of gels in which the restrictive dimensions are those of the interstices between gel fibres or particles. In both cases molecular sieving reflects geometric exclusion of large molecules from a fraction of the membrane volume accessible to water and small molecules.
Two elegant studies have recently focused attention on the role played by molecular charge as a determinant of glomerular permeability, providing new insight into the factors determining permeability to macromolecules and a new impetus to investigation. The glomerular epithelial cells are rich in sialic acid residues and are thereby endowed with a thick anionic coat, suggesting that an electrostatic barrier is thus posed to filtration of negatively charged plasma proteins.
Rennke et al. (1975) used ferritins as electron dense tracers and electron microscopy to demonstrate that increasing positive charge on ferritin molecules resulted in an increased permeation through the glomerular basement membrane, without a change in the molecular size or configuration of ferritin molecule. Chang et al. (1975) used dextran molecules and micropuncture to demonstrate a similar phenomenon.
They pointed out that the renal clearance of albumin, a polyanion, is much less than that of dextrans despite an identical molecular radius of about 36 A. An anionic dextran polymer, dextran sulphate, had a fractional clearance reduced to that of albumin. The results suggest that a major portion of the barrier function of the glomerular capillary wall may be ascribed to electrostatic repulsion of charged macromolecules.
Rennke et al. (1975) suggest an additional mechanical barrier operating in series with the endothelium and glomerular basement membrane, since even the heavity cationized ferritin accumulated proximal to the level of the filtration slit diaphragm without entering the urinary spaces. Debate continues on the principal filtration barrier (Farquhar 1975). Such observations are not possible, of course, with physiologic techniques.
After correction for the influence of Donnan effects of the non-filtered protein on charged particles, the concentrations show remarkable conformity with that predicted for a passive, freely permeable membrane. Dextrans and inulin with a molecular weight of 5,000 or less also appear in the filtrate in concentrations which indicate that the membrane is freely permeable to molecules of this size. Conversely, normal plasma proteins are present in the filtrate only in concentrations at the level of the threshold sensitivity for detection.
Bayliss et al. (1933) found in the cat, rabbit and dog that proteins with a molecular weight over 68,000, such as serum albumin and globulins, were not excreted in the urine, whereas smaller proteins such as gelatin, the molecular weight of which ranges from l7,000 to 57,000. Hence-Jones protein with a molecular weight of 40,000, and haemoglobin with a molecular weight of 68,000 appeared in the urine after intravenous administration.
Since that time many studies in animals and in man have demonstrated that molecules which can be administered in graded size, such as dextran or polyvinylpyrrolidone, appear in the urine in approximate relationship to their molecular weight and size (Renkin & Gilmore l973) see also Chapter 13.
Increasing restriction to penetration by solutes of increasing molecular size is a property both of membrane structures which have pores of approximately the dimensions of the solutes in an otherwise impermeable matrix, and of gels in which the restrictive dimensions are those of the interstices between gel fibres or particles. In both cases molecular sieving reflects geometric exclusion of large molecules from a fraction of the membrane volume accessible to water and small molecules.
Two elegant studies have recently focused attention on the role played by molecular charge as a determinant of glomerular permeability, providing new insight into the factors determining permeability to macromolecules and a new impetus to investigation. The glomerular epithelial cells are rich in sialic acid residues and are thereby endowed with a thick anionic coat, suggesting that an electrostatic barrier is thus posed to filtration of negatively charged plasma proteins.
Rennke et al. (1975) used ferritins as electron dense tracers and electron microscopy to demonstrate that increasing positive charge on ferritin molecules resulted in an increased permeation through the glomerular basement membrane, without a change in the molecular size or configuration of ferritin molecule. Chang et al. (1975) used dextran molecules and micropuncture to demonstrate a similar phenomenon.
They pointed out that the renal clearance of albumin, a polyanion, is much less than that of dextrans despite an identical molecular radius of about 36 A. An anionic dextran polymer, dextran sulphate, had a fractional clearance reduced to that of albumin. The results suggest that a major portion of the barrier function of the glomerular capillary wall may be ascribed to electrostatic repulsion of charged macromolecules.
Rennke et al. (1975) suggest an additional mechanical barrier operating in series with the endothelium and glomerular basement membrane, since even the heavity cationized ferritin accumulated proximal to the level of the filtration slit diaphragm without entering the urinary spaces. Debate continues on the principal filtration barrier (Farquhar 1975). Such observations are not possible, of course, with physiologic techniques.